YWHAE silencing induces cell proliferation, invasion and migration through the up-regulation of CDC25B and MYC in gastric cancer cells: new insights about YWHAE role in the tumor development and metastasis process.

Mariana Ferreira Leal,Giovanny Rebouças Pinto,Caroline Aquino Moreira-Nunes,Leticia Martins Lamarão,Juan Antonio Rey,Helem Ferreira Ribeiro,Raquel Carvalho Montenegro,Marília Cardoso Smith,Rommel Rodriguez Burbano,Danielle Queiroz Calcagno,Paulo Pimentel Assumpção

doi:10.18632/oncotarget.13381

Abstract

We previously observed reduced YWHAE (14-3-3ε) protein expression in a small set of gastric cancer samples. YWHAE may act as a negative regulator of the cyclin CDC25B, which is a transcriptional target of MYC oncogene. The understanding of YWHAE role and its targets is important for the better knowledge of gastric carcinogenesis. Thus, we aimed to evaluate the relationship among YWHAE, CDC25B, and MYC in vitro and in vivo. For this, we analyzed the YWHAE, CDC25B, and MYC expression in YWHA-silenced, CDC25B-silenced, and MYC-silenced gastric cancer cell lines, as well as in gastric cancer and non-neoplastic gastric samples. In gastric cancer cell lines, YWHAE was able to inhibit the cell proliferation, invasion and migration through the reduction of MYC and CDC25B expression. Conversely, MYC induced the cell proliferation, invasion and migration through the induction of CDC25B and the reduction of YWHAE. Most of the tumors presented reduced YWHAE and increased CDC25B expression, which seems to be important for tumor development. Increased MYC expression was a common finding in gastric cancer and has a role in poor prognosis. In the tumor initiation, the opposite role of YWHAE and CDC25B in gastric carcinogenesis seems to be independent of MYC expression. However, the inversely correlation between YWHAE and MYC expression seems to be important for gastric cancer cells invasion and migration. The interaction between YWHAE and MYC and the activation of the pathways related to this interaction play a role in the metastasis process.

Highlights

Gastric cancer (GC) is one of the most common causes of cancer death in the World [1]
YWHAE may act as a negative regulator of the cyclin CDC25B, which is a transcriptional target of MYC oncogene
YWHAE silencing induces GC cell proliferation, invasion and migration small interfering RNA (siRNA) decresead YWHAE expression in more thand 80% in ACP03 and in more than 90% in AGP01 and ACP02 cell lines (Figure 2A–2B)

Summary

Introduction

Gastric cancer (GC) is one of the most common causes of cancer death in the World [1]. Seven 14-3-3 genes encode nine protein isoforms, including two phosphorylated forms (α and δ) [3, 4]. The 14-3-3 proteins are mainly dimeric within the cell and are able to bind several sites within a target or act as a bridge between proteins [5,6,7]. 14-3-3 proteins can interact with hundreds of proteins, including cdc phosphatase [4, 5, 7, 8]. The precise function of 14-3-3 proteins is not fully understand. These proteins seem to play a role as molecular scaffolds [4] and regulate different biologic processes, including apoptosis, mitogenic signal transduction, and cell cycle (for reviews, see references [5, 9, 10])

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